The bacterium that causes tuberculosis (TB), Mycobacterium tuberculosis (M.tb), has infected one third of the world's population. Infection occurs when the pathogen is inhaled, following exposure to a patient with lung TB. 10% of infected persons progress to disease, while 90% never do. We don't understand why some people develop disease, while others do not: this is the focus of this application. To address protection against TB, we have established a cohort of 6,363 South African adolescents. 53% were infected with M.tb at baseline. During 2 years of follow-up, 76 of these participants developed TB disease. As blood was collected and stored every 6 months, we have a unique opportunity to compare host responses between adolescents who developed disease and those who have remained healthy. We will have two approaches to defining protection. Our first focus will be on T cells, which are immune cells shown to be critical for protection against TB. Current assays focus on limited aspects of the T cell response, but have not been successful in defining protection. We have devised a new paradigm - we hypothesize that a model including multiple T cell functional attributes plus their regulation by multiple immune cells will define protection. We propose that relative immune quiescence, i.e., an optimal but relatively silent immune response, is associated with protection. We and others have preliminary data to suggest that too much inflammation, or too much activation of the immune system, may be detrimental. The rationale for our second focus is that our knowledge of host control of M.tb infection remains incomplete - we therefore propose an unbiased approach that will facilitate discovery of novel pathways involved in protection. We will assess genome-wide gene expression in blood cells, including purified immune cell populations, to delineate new pathways involved in protection. Our preliminary studies of protection against TB in infants have shown the incredible power of this approach. The longitudinal nature of the adolescent cohort, and state-of-the-art bioinformatic approaches, afford unique muscle for uncovering host determinants of protection. We will immediately validate findings by studying further groups of adolescents, from the same cohort. This will be followed by mechanistic studies aimed at understanding how newly described markers may act to protect us against TB. Knowledge of host determinants of protection against TB disease could impact TB control in many ways. For example, targeted prophylactic therapy for infected persons could be implemented, as well as rapid clinical testing of novel TB vaccines. Knowledge gained will also stimulate development of new vaccines and drugs against TB.